The skin is formed from the stratum corneum, which is the outermost layer, the epidermis, the dermis, and subcutaneous tissue connective tissue, and the stratum corneum, which is formed from a dead cell layer and a lipid bilayer, normally shows a strong barrier function toward many materials. In the epidermal layer, antigen-presenting cells called Langerhans' cells are present and carry out an immune function. Mucous membranes, which cover the oral cavity, the nasal cavity, respiratory organs, digestive organs, and genital organs, are also a boundary with the external environment and have the same structure as that of the skin except that there is no stratum corneum, which is the outermost layer of the skin. Mucous membranes are in contact with various types of foreign substances during food ingestion, breathing, etc., and are a main route for, for example, pathogenic microorganisms to enter the interior of a host body. Because of this, the immunological defense mechanism in the mucous membrane is also important as a biological barrier.
Langerhans' cells capture a protein antigen that has entered the interior of the skin, decompose it internally, and express a peptide fragment on an MHC molecule. The MHC-peptide complex moves from an afferent lymphatic vessel to a subcortical layer of a regional lymph node and contacts a T cell via an interdigitating cell. Due to the Langerhans' cells moving in this way, the antigen is efficiently transmitted from the skin to TH cells present within the lymph node. Langerhans' cells have an abundance of MHC class II molecules, which are necessary for presenting an antigen to the TH cells.
An adjuvant is a material that enhances immunogenicity, and when it is administered with an antigen, the response to the antigen increases. In vaccination, an adjuvant is useful from the viewpoint of reduction in the vaccine dose and the number of times of administration. There has been a large amount of research into adjuvants, and as some examples an aluminum salt, an immune-stimulating complex (ISCOM), a bacteria-derived material, etc. are known. However, many of these adjuvants are directly administered subcutaneously or intramuscularly, and in such a case a tissue disorder such as contact hypersensitivity, subcutaneous nodules, or granuloma is induced. There is therefore a high demand for a safe and efficiently administrable adjuvant and preparation in immunostimulation such as human vaccination.
With regard to the adjuvant, a large number of vaccine formulations that contain an attenuated pathogen or protein subunit antigen have been developed so far. In most cases, the conventional vaccine preparations contain an adjuvant for enhancing the immune response. For example, an adjuvant forming a depot (Depot) is well known. This adjuvant makes an administered antigen be absorbed or precipitated, thus forming a depot at the injection site. Typical examples of the depot-forming adjuvant include an aluminum compound such as aluminum phosphate or aluminum hydroxide gel and an oil-in-water emulsion.
However, although the depot-forming adjuvant enhances the antigenicity, since it causes a local tissue disorder such as erythema, contact hypersensitivity, or granuloma formation when it is administered subcutaneously or intramuscularly, there is a problem in terms of application. Furthermore, in transdermal administration, there is a problem with the absorbability of an aluminum salt. Such problems with transdermal absorbability of the adjuvant itself are also common problems for an immune-stimulating complex (ISCOM), a bacteria-derived material, or a cytokine as an adjuvant. For example, it is known that muramyldipeptide causes, when injected, a pyretic reaction having symptoms similar to those of influenza, Reiter's syndrome, general joint pain, in some cases anterior uveitis, arthritis, or urethritis.
As hereinbefore described, adjuvants often cause severe local tissue disorder when subcutaneously or intramuscularly administered. In order to avoid this local tissue disorder, transdermal administration has been considered, but conventional adjuvants are either macromolecules, for example, an immune-stimulating complex (ISCOM), a bacteria-derived material, etc., or an aluminum compound, etc., none of which are compounds that are suitable for transdermal administration.
Moreover, in recent years, as means for enhancing permeation, external administration employing iontophoresis or a device equipped with microneedles has been investigated, but if, in addition to an antigen, which is a macromolecule, the adjuvant also has poor absorbability, it is currently impossible to make the antigen and the adjuvant permeate efficiently.
For example, Patent Publication 1 discloses iontophoresis as a method for delivering a macromolecular antigen to the interior of a skin cell, but there is no description of an adjuvant.
Patent Publication 2 discloses a skin patch having a microprojection array and a reservoir containing an antigen agonist and an immune response-enhancing adjuvant, and its application method for vaccination of an animal (e.g. man). However, the adjuvants described in this publication are limited to metal salts and macromolecules (peptides, etc.), and there is no description of an adjuvant having skin permeability.
Patent Publication 3 discloses, as a low molecular weight adjuvant to be administered by injection, a long chain aliphatic alcohol, an ester thereof with a C1 to C6 alkanoic acid, and a specific ester of a long chain fatty acid, an alkanol, and a polyol, but there is no description of the immune response thereof toward an antigen by transdermal administration.
Moreover, Patent Publication 4 discloses a local administration method that includes a step of administering a mixture of an antigen and an oleophilic solvent, and a step of administering, after the above administration, a material for inducing migration of Langerhans' cells. However, in accordance with this publication, the material for promoting the induction for Langerhans' cells is limited to a divalent unsaturated carboxylic acid ester, such as dibutyl phthalate, represented by the formula below.
(in the formula, R3 and R4 may be bonded to form a cyclic ring, and R1 and R2 are independently an alkyl side chain containing 1 to 16 carbon atoms).
Patent Publication 5 discloses a dry preparation containing cholera toxin or a related ADP-ribosylation toxin as an adjuvant. In such a preparation, it is thought that the cholera toxin or related ADP-ribosylation toxin as an adjuvant permeates the skin and induces an immune response. On the other hand, there is little information on the safety of such adjuvants, and there are the defects of the permeability toward skin being low due to them being macromolecules and the cost being high.    [Patent Publication 1] JP, A, (PCT) 2002-535100    [Patent Publication 2] JP, A, (PCT) 2004-538048    [Patent Publication 3] JP, A, (PCT) 2004-526757    [Patent Publication 4] JP, A, (PCT) 2002-512186    [Patent Publication 5] JP, A, (PCT) 2001-517233
As described above, conventional adjuvants used for injection have problems such as local tissue disorders. Furthermore, transdermal absorption preparations are characterized by excellent safety and simplicity compared with an injection, but there are very few materials, in particular low molecular weight compounds, that efficiently exhibit the action of a transdermally administered adjuvant. Moreover, in the clinical field there is a strong desire for an adjuvant that can be provided at low cost.